Congestive heart failure, regardless of its etiology, is characterized by a weakness of the myocardial tissue of the left and/or right ventricle of the heart to pump and thereby circulate blood into systemic and/or pulmonary circulations. It is accompanied by circulatory and neurohumoral changes which result in failure to deliver sufficient blood and oxygen supply to peripheral tissues and vital organs. If left untreated, the health of a patient with congestive heart failure could progress to the point where the disease would be fatal.
Survival data from patients with overt congestive heart failure in the Framingham Heart Study indicate persisting high lethality without significant temporal prognostic improvement during the 40 year period 1948-1988 (Ho K K L, Anderson K M, Kannel W B, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993; 88: 107-115). Over the years a precise definition of heart failure has remained elusive. Heart failure is generally characterized by an inadequacy of the heart, usually in association with elevated central cardiac filling pressures, to meet the metabolic demands of peripheral organs and tissues either at rest or during stress. The lack of a uniformly accepted definition of heart failure and the myriad of patient subsets within this heterogenous diagnosis present a considerable challenge to the practicing physician selecting therapy.
The term "cardiomyopathy" is used to define diseases of the myocardium of either known or unknown etiology. In approximately 75-80% of heart failure patients coronary artery disease is the underlying cause and is designated "ischemic cardiomyopathy". Table 1 lists most of the etiologies and associations of cardiomyopathy that are not attributed to underlying coronary artery disease (CAD), and are designated "non-ischemic cardiomyopathies".
TABLE 1 ______________________________________ Non-Ischemic Causes of Cardiomyopathy ______________________________________ 1) Idiopathic 8) Infectious (Viral, bacterial, 2) Granulomatous disease rickettsial, Protozoal) (Idiopathic, Sarcoidosis, 9) Metabolic/endocrine (Acromegaly, Giant cell, Wegner's) Hypothyroidism, Pheochromocytoma, 3) Collagen vascular disease diabetes, beriberi, selenium (Lupus ethythematosus, deficiency, Kwashiorkor, dermatomyositis) hemochromatosis, thiamine 4) Neuromuscular disease deticiency) 5) Hypertension 10) Polyarteritis nodosa (Scleroderma) 6) Cardiac valvular disease 11) Toxins (alcohol, radiation arsenic, 7) Genetic or familial cobalt, lead, carbon tetrachloride, cardiomyopathy carbon monoxide, amphetamines, cocaine, anthracyclines, cyclophosphamide) 12) Peri- or Post-partum cardiomyopathy 13) Allergic or hypersensitivity 14) Myocarditis ______________________________________
The underlying cause of cardiomyopathy rather than the severity of the heart failure syndrome may influence the response to drug therapy. Some evidence exists to suggest that preferential benefit accrues to patients with non-ischemic cardiomyopathy as opposed to those with heart failure due to coronary artery disease. In the Veterans Affairs Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure only patients with heart failure not due to myocardial ischemia seemed to derive a benefit from amiodarone, a class III antiarrhythmic compound with beta-blocking properties. (Singh S N, Fletcher R D, Gross Fisher S, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995; 333: 77-82). Similarly, another trial using the beta blocker bisoprolol, Cardiac Insufficiency Bisoprolol Study (CIBIS), found no significant risk reduction in patients with ischemic heart failure but did find a benefit in those with non-ischemic heart failure. (CIBIS Investigators and Committees. A randomized trial of Beta blockade in heart failure: the Cardiac Insufficiency bisoprolol Study (CIBIS). Circulation 1994; 90: 1765-73).
Amlodipine, 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)4-(2-chlorophenyl)-1,4-dihydro-6-m ethylpyridine-3,5-dicarboxylate, see U.S. Pat. No. 4,572,909, and its pharmaceutically acceptable acid addition salts are calcium channel blockers known for their effectiveness in the treatment, inter alia, of congestive heart failure, see U. S. Pat. No. 5,155,120 to Lazar et al. Amlodipine is currently marketed as the besylate salt, see U.S. Pat. No. 4,879,303. The teachings of U.S. Pat. Nos. 4,572,909, 4,879,303 and 5,155,120 are incorporated herein by reference.
ACE inhibitors are well known in the art for their activity in inhibiting angiotensin converting enzyme, thereby blocking conversion of the decapeptide angiotensin I to angiotensin II. The principal pharmacological and clinical effects of ACE inhibitors arise from suppression of synthesis of angiotensin II. Angiotensin II is a potent pressor substance and, therefore, blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related. ACE inhibitors are effective antihypertensive agents in a variety of animal models and are clinically useful for the treatment of hypertension in humans.
ACE inhibitors are also employed for the treatment of heart conditions such as hypertension and heart failure. It is known that at least some ACE inhibitors can improve (i.e., decrease) morbidity and mortality in patient populations with heart conditions.
International application PCT/US92/03873, published as WO 92/20342, discloses pharmaceutical compositions containing a combination of an angiotensin II antagonist and a calcium channel blocker for use in the treatment of hypertension and congestive heart failure. The publication states that the particular compositions can further contain antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors.
U.S. patent application Ser. No. 08/405,108 filed Mar. 16, 1995, abandoned in favor of International PCT Application No. PCT/IB96/00145 filed Feb. 26, 1996 published as WO 96/28185, now U.S. patent application Ser. No. 08/894,800 by the instant inventor and assigned to the assignee hereof, discloses a composition comprising amlodipine, a pharmaceutically acceptable salt of amlodipine or felodipine and an ACE inhibitor and, optionally, a diuretic and/or digoxin; a method for reducing morbidity and/or mortality in a mammal with congestive heart failure; and a method for treating congestive heart failure, both methods comprising administering a combination of amlodipine, a pharmaceutically acceptable salt of amlodipine or felodipine and ACE inhibitor and, optionally, a diuretic and/or digoxin.